A protein responsible for protecting nerve cells can become embedded in other substances in the brains of Huntington’s patients, preventing it from performing its neuroprotective work, Spanish researchers report.

Another important finding was that the areas where the ATF5 protein are embedded also contain clusters of the faulty huntingtin protein associated with the disease. Abnormal huntingtin causes Huntington’s by killing nerve cells, scientists believe.

The study’s findings have implications for the development of treatments for the disease.

Scientists call substances that are embedded in other substances inclusions. The Spanish study dealt with ATF5 inclusions, or structures that prevent the protein from doing its protective job. The inclusions leave nerve cells more vulnerable to dying, the researchers said.

In earlier research, the researchers showed that ATF5 in mouse brains acts to protect nerve cells during epileptic seizures.

The new study showed that both healthy people and those with Huntington’s have the protein in their brains. In Huntington’s patients the protein is confined to nerve-cell structures resembling those containing damaging huntingtin. The team made the discovery by examining the brains of patients who died.

Using different dyes for ATF5 and faulty huntingtin, the researchers demonstrated that AFT5 had accumulated in the same spot as the abnormal protein.

They also found lower levels of soluble ATF5 in key areas of patients’ brains, with particularly low levels in the cortex, an area crucial to cognition and other higher functions. The lower levels correlated with lower levels of a factor that prevents cell death.

The team used a roundworm model of toxicity to test the idea that the embedding of ATF5 speeds up nerve cell death. The model involved toxicity caused by proteins with repeat stretches of glutamine — the pattern found in faulty huntingtin.

The experiments confirmed that lack of ATF5 makes nerve cells more vulnerable to the toxic effects of abnormal huntingtin protein. Researchers also found that ATF5 protected lab-grown cells mimicking Huntington’s.

The findings suggested that developing compounds that can increase levels of soluble ATF5 could be a way to treat Huntington’s.

Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.

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